Aug 2026· Journal of Biomolecular Structure and Dynamics· pp.
1-15
· 0 citations· 43 references
Medicine
TL;DR
This study elucidates the mechanism of ADAM10/PD-L1 interaction in the pancreatic adenocarcinoma cell line, PANC-1, using cellular assays, molecular docking, and molecular dynamics simulations to elucidate how ADAM10 recognizes and interacts with PD-L1, facilitating its cleavage.
Abstract
Targeting the immune checkpoint programmed cell death-ligand 1 (PD-L1) faces diverse challenges against pancreatic ductal adenocarcinoma (PDAC), the most common type of cancer-related death. Shedding of PD-L1 from the tumor cell surface by A Disintegrin And Metalloprotease 10 (ADAM10) may impede the function of antitumor immune cells. Understanding the molecular mechanisms behind this interaction is urgently needed. This study elucidates the mechanism of ADAM10/PD-L1 interaction in the pancreatic adenocarcinoma cell line, PANC-1, using cellular assays, molecular docking, and molecular dynamics (MD) simulations. Cellular assays validated that ADAM10 interacts with PD-L1 and sheds the PD-L1 from the cell surface, generating soluble PD-L1 (sPD-L1). Concurrently, the docking results identified critical residues and potential contact points, providing strong evidence for a stable and specific interaction between ADAM10 and PD-L1. The molecular dynamics (MD) simulations further confirmed the structural integrity of the ADAM10/PD-L1 complex, predicting its compactness and stability. These results elucidate how ADAM10 recognizes and interacts with PD-L1, facilitating its cleavage. Future work can leverage these findings to develop potent cancer immunotherapies that inhibit the ADAM10/PD-L1 interaction and the generation of soluble molecules.
Background/Objectives. Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint protein that enables tumors to evade immune surveillance by suppressing T cell activation. Monoclonal antibodies are currently used to modulate PD-1/PD-L1 interactions. However, several immune-associated adverse effects were ascribed to those treatments. This led to the necessity for small-molecule alternatives like BMS-202. Methods. In this study, we investigated the temporal dynamics of cell-surface PD-L1 in response to the small-molecule dimerizer BMS-202. Treatment with a non-cytotoxic concentration of BMS-202 at 5 µM triggered a transient reduction in surface PD-L1 concentration, reaching its lowest level at 15 min. In the attempt to characterize the fate of PD-L1 following exposure to the BMS-202 dimerizer, we employed a low-pH wash internalization assay. Results. The results demonstrated a transient increase in intracellular PD-L1 within 5–15 min of compound exposure, followed by rapid recovery of surface PD-L1 levels. These findings suggest that BMS-202-induced changes in surface PD-L1 are acute and reversible, with levels returning to baseline within 24 h post-exposure. Conclusions. These findings reveal a dynamic regulatory mechanism where small-molecule-induced dimerization triggers rapid protein trafficking and transient surface depletion. Understanding these temporal dynamics is essential for the development of next-generation small-molecule immune checkpoint inhibitors.
Gohar Sevoyan, Daniel Polianczyk, Siranuysh Grabska et al.· Biomedicines· 0 citations
Programmed death-ligand 1 (PD-L1) has long been characterized as a membrane-bound immune checkpoint ligand that suppresses antitumor immunity through engagement with PD-1 on T cells. This canonical understanding has underpinned the development of therapeutic antibodies that have revolutionized cancer treatment. However, PD-1/PD-L1 immunotherapy still has limitations such as poor response rates and post-treatment resistance. Notably, emerging evidence reveals that the roles of PD-L1 extend beyond its membrane-bound form, with substantial pools residing in the cytoplasm, nucleus, organelles, and extracellular vesicles. These intracellular PD-L1 populations perform distinct, often immune-independent functions including transcriptional regulation, mRNA stability control, DNA damage response modulation, and metabolic reprogramming. This review examines the subcellular localization of PD-L1, the mechanisms governing its trafficking and compartmentalization, its compartment-specific biological functions, and the corresponding clinical significance. Understanding the full spectrum of PD-L1 biology is essential for developing more effective immunotherapeutic approaches and promoting individualized treatment strategies.
Youliang Zhao, Yaqian Qu, Changfu Hao et al.· International Journal on Bio...· 0 citations
BACKGROUND
Programmed death-ligand 1 (PD-L1) has traditionally been regarded as a membrane-bound immune checkpoint ligand that suppresses antitumor T-cell activity through PD-1 engagement. Although this framework remains fundamental, it is no longer sufficient to capture the full biologic and clinical complexity of PD-L1 in cancer. Accumulating evidence indicates that PD-L1 is not a static surface marker, but a dynamically regulated molecular hub positioned at the intersection of inflammatory signaling, tumor-cell adaptation, and immune escape.
MAIN BODY
Within the tumor microenvironment, inflammatory cues including interferons, TNF-α, IL-6, Toll-like receptor signaling, hypoxia, and therapy-induced stress regulate PD-L1 through transcriptional, post-transcriptional, and post-translational mechanisms. These inputs do not merely increase PD-L1 abundance. They shape PD-L1 protein fate through glycosylation, ubiquitination, palmitoylation, endocytic trafficking, recycling, and degradation, thereby determining membrane abundance, localization, and activity. Beyond canonical PD-1 ligation, PD-L1 can also exert tumor-intrinsic effects, mediate exosomal immunosuppressive communication, and adopt context-dependent nuclear functions linked to stress adaptation and treatment resistance. In turn, PD-L1 participates in self-reinforcing circuits involving exhausted T cells, myeloid suppressor populations, stromal signaling, additional checkpoint-sensitive immune compartments, and therapy-driven adaptive resistance. We distinguish validated from emerging PD-L1 states across experimental models and human tumors.
CONCLUSION
A framework linking inflammatory input, PD-L1 protein fate, functional output, and feedback provides an integrated view of PD-L1 biology in cancer. Translationally, this framework argues for moving beyond single-point PD-L1 testing toward integrated assessment of inflammatory context, spatial organization, and dynamic PD-L1 states, while supporting mechanism-guided combination strategies targeting the PD-L1 axis.
Kuan Liang, Ziang Jia, Haiwen Lu et al.· Discover Oncology· 0 citations
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options, driven in part by its immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs) and neutrophils (TANs) contribute to tumor progression and immune evasion. A Disintegrin and Metalloproteinase 8 (ADAM8), a zinc-dependent protease, is strongly upregulated in PDAC and correlates with poor clinical outcomes, suggesting a regulatory role in tumor progression. Wild-type (WT) and Adam8 knockout (A8KO) PDAC cell lines were generated using the CRISPR-Cas9 technique, and PDAC mouse models with or without Adam8 expression were established to investigate the role of ADAM8 in tumor and immune cells. In vitro assays, including Western blotting, qPCR, migration and invasion assays, proliferation assays, ELISA, cytokine and proteome analyses, as well as co-culture experiments with PDAC cells and either macrophages or neutrophils, were employed to assess the effects of ADAM8 on tumor–immune cell crosstalk. In parallel, in vivo WT and A8KO KPC models were generated, genotyped, and monitored to evaluate the impact of ADAM8 on survival, tumor growth, and immune cell recruitment within the PDAC TME. ADAM8 deletion reduced tumor cell proliferation and migration, associated with reduced activation of FAK/Src/STAT3 signaling and altered secretion of cytokines including GM-CSF, M-CSF, ICAM-1, and TNF-α. Co-culture assays demonstrated that ADAM8 enhanced reciprocal signaling between tumor cells and TAMs/TANs, promoting pro-oncogenic activation. Migration assays and in vivo analyses revealed that ADAM8 facilitated recruitment of macrophages and neutrophils in PDAC TME, while Adam8KO tumors exhibited reduced immune infiltration and altered macrophage polarization. Our findings demonstrate that ADAM8 promotes PDAC aggressiveness by enhancing tumor cell proliferation and migration, activating FAK/Src/STAT3 signaling, and driving macrophage and neutrophil recruitment through cytokine regulation. By orchestrating both tumor-intrinsic pathways and tumor–immune interactions, ADAM8 emerges as a key determinant of PDAC progression and a systemic target for therapeutic intervention.
Kimia Zandieh, L. Cook, Kai Zhao et al.· Cellular Oncology· 0 citations
Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are critical immune checkpoints that dynamically maintain the balance between immune tolerance and immune activation. Immune checkpoint blockade targeting the PD-1/PD-L1 axis can restore T cell-mediated antitumor immunity and has shown remarkable clinical efficacy in the treatment of various solid tumors. However, owing to the complexity of the underlying mechanisms and the limitations of current predictive biomarkers, only a subset of patients derives durable benefit from this therapy. Although conventional paradigms have primarily regarded T lymphocytes as the main effectors of PD-1/PD-L1 signaling, accumulating evidence indicates that macrophages also play indispensable roles in shaping PD-1/PD-L1-mediated immunosuppressive tumor microenvironments, thereby extending the traditional understanding of this pathway. A deeper understanding of the functional roles and regulatory mechanisms of PD-1+/PD-L1+ macrophages in specific immune contexts is therefore essential for optimizing immunotherapeutic outcomes. In this review, we comprehensively summarize the regulatory mechanisms governing PD-1/PD-L1 expression in macrophages and their biological functions, and discuss the potential of PD-1+/PD-L1+ macrophages as prognostic biomarkers and therapeutic targets, and further examine targeted intervention strategies for this macrophage subset as well as their clinical diagnostic value.
Jinjing Wu, Dan Zhou, Kunpeng Jiang et al.· Biochemical Pharmacology· 0 citations
CP-1 exhibits balanced, dual-nanomolar inhibitory activity against PD-L1 and CD73 and displays potent immunomodulatory effects at the cellular level and serves as a promising lead candidate for developing novel bifunctional agents to advance tumor immunotherapy.
Jing-Jing Du, Sen Wu, Shiyun Cheng et al.· Frontiers in Immunology· 0 citations
